Neurodegenerative disease encompasses a range of seriously debilitating conditions including Parkinson's disease, amyotrophic lateral sclerosis (ALS, "Lou Gehrig's disease"), multiple sclerosis, Huntington's disease, Alzheimer's disease, diabetic retinopathy, multi-infarct dementia, macular degeneration and the like. These conditions are characterized by a gradual but relentless worsening of the patient's condition over time. The mechanisms and causes of these diseases are becoming better understood and a variety of treatments have been suggested. One of these neurodegenerative conditions, Parkinson's disease, is associated with abnormal dopamine depletion in selected regions of the brain.
Recent summaries of the state of understanding of Parkinson's disease are provided by Marsden. C. D., in "Review Article--Parkinson's Disease" Lancet (Apr. 21, 1990) 948-952 and Calne, D. B., in "Treatment of Parkinson's Disease" NEJM (Sep. 30, 1993) 329:1021-1027. As these reviews point out, dopamine deficiency was identified as a key characteristic of Parkinson's disease, and the destruction of the dopaminergic nigrostriatal pathway paralleled dopamine depletion in Parkinson's patients.
Rapid development of Parkinson's-like symptoms in a small population of illicit drug users in the San Jose, Calif. area was linked to trace amounts of a toxic impurity in the home-synthesized drugs. Subsequent studies in animal models, including monkeys, demonstrated that 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) was the cause of the Parkinson's-like symptoms which developed in the illicit drug users, as reported by J. W. Langston et al., in "Chronic Parkinsonism in Humans Due to a Product of Meperidine-Analog Synthesis" Science (Feb. 25, 1983) 219, 979-980. These early findings and the many studies that they stimulated led to the development of reliable models for Parkinson's disease, as reported by Heikkila, R. E., et al., in "Dopaminergic Neurotoxicity of 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine in Mice" Science (Jun. 29, 1984) 224:1451-1453; Burns, R. S., et al., in "A Primate Model of Parkinsonism . . . " Proc. Natl. Acad. Sci USA (1983) 80:4546-4550; Singer, T. P., et al., "Biochemical Events in the Development of Parkinsonism . . . " J. Neurochem. (1987) 1-8; and Gerlach, M. et al., "MPTP Mechanisms of Neurotoxicity and the Implications for Parkinson's Disease" European Journal of Pharmacology (1991) 208:273-286. These references and others describe studies to help explain the mechanism of how the administration of MPTP to animals gives rise to motor defects characteristic of Parkinson's disease. They clearly indicate that MPTP was the cause of the Parkinson's-like symptoms that developed in the humans who had used the tainted illicit drugs and that similar motor deficits were found in other primates and other test animals which had been dosed directly with MPTP. They further point out that the administration of MPTP induces a marked reduction in the concentration of dopamine in the test subjects.
These findings have led to the development of an assay for agents effective in treating dopamine-associated neurodegenerative disorders, such as Parkinson's disease. In this assay, test animals are given an amount of MPTP adequate to severely depress their dopamine levels. Test compounds are administered to determine if they are capable of preventing the loss of dopamine in the test animals. To the extent that dopamine levels are retained, a compound can be considered to be an effective agent for slowing or delaying the course of neurodegenerative disease, e.g., Parkinson's disease.
Another assay for agents effective in treating dopamine-associated neurodegenerative disorders has been developed. In this assay, the striatum of test animals is injected with the neurotoxicant, 6-hydroxydopamine. 6-Hydroxydopamine has a dopamine-depleting action and is widely accepted as a model for these conditions. Test compounds are administered to determine if they are capable of preventing or reducing the loss of dopamine in the test animals. Again, to the extent that dopamine levels are retained, a compound can be considered an effective agent.
Mitochondrial function is associated with many neurodegenerative diseases such as ALS, Huntington's disease, Alzheimer's disease, cerebellar degeneration, and aging itself (Beal, M. F. in Mitochondrial Dysfunction and Oxidative Damage in Neurodegenerative Diseases, R. G. Landes Publications Austin, Tex., 1995 at, for example, pages 53-61 and 73-99). Mitochondrial damage is the mechanism by which MPTP depletes dopamine concentrations in the striatum (Mizuno, Y., Mori, H., Kondo, T. in "Potential of Neuroprotective Therapy in Parkinson's Disease" CNS Drugs (1994) 1:45-46). Thus, an agent which protects from mitochondrial dysfunction caused by MPTP could be useful in treating diseases of the central nervous system in which the underlying cause is mitochondrial dysfunction.
Models are also available for determining the efficacy of materials in the treatment of other neurodegenerative conditions. For example, the efficacy of compounds against Alzheimer's disease can be determined in cell culture tests. In two such tests, compounds are evaluated for their ability to protect against the amyloid .beta.(25-35) or glutamate-induced neuronal cell loss in rat embryonic hippocampal neuronal/astrocytes cultures. In another test, compounds are evaluated for their ability to intervene in amyloid .beta.(1-40) beta pleated sheet formation. Compounds which have this effect can be considered candidates for treating Alzheimer's disease.
While other benzamide compounds are known, their utility heretofore has generally been as intermediates in chemical syntheses or in fields unrelated to the present invention. Slight structural changes yielded large differences in efficacy and toxicity. The vast majority of benzamide compounds have little or no activity in our screens. However, there are reports of biological activity for other, structurally different benzamides. These reports include:
El Tayar et al., "Interaction of neuroleptic drugs with rat striatal D-1 and D-2 dopamine receptors: a quantitative structure--affinity relationship study" Eur. J. Med. Chem. (1988) 23:173-182;
Monkovic et al., "Potential non-dopaminergic gastrointestinal prokinetic agents in the series of substituted benzamides" Eur. J. Med. Chem. (1989) 24:233-240;
Banasik et al., "Specific inhibitors of poly(ADP-Ribose) synthetase and mono(ADP-ribosyl)transferase" J. Biol. Chem. (1992) 267:1569-1575;
Bishop et al., "Synthesis and in vitro evaluation of 2,3-dimethoxy-5-(fluoroalkyl)-substituted benzamides: high-affinity ligands for CNS dopamine D.sub.2 receptors" J. Med. Chem. (1991) 34:1612-1624;
Hogberg et al., "Potential antipsychotic agents. 9. Synthesis and stereoselective dopamine D-2 receptor blockade of a potent class of substituted (R)-N-benzyl-2-pyrrolidinyl)methyl!benzamides. Relations to other side chain congeners" J. Med. Chem. (1991) 34:948-955;
Katopodis et al., "Novel substrates and inhibitors of peptidylglycine .alpha.-amidating monooxygenase" Biochemistry (1990) 29:4541-4548; and
Rainnie et al., "Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal" Science (1994) 263:689-690.
Other benzamide-containing pharmaceutical compositions and their use to treat or protect against neurodegenerative conditions were disclosed in commonly owned U.S. Pat. No. 5,472,983.